Low circulating levels of vitamin D [25-(OH)D] have been associated with various adult onset cancers. However, studies of childhood cancer have not been conducted despite compelling experimental and epidemiologic evidence suggesting that reduced vitamin D during gestational development may be a risk factor, particularly for childhood brain tumors (CBT). For CBT, the in utero period of development has been shown to be a critical time window of exposure. Neonatal dried blood spots (DBS) collected and archived as part of newborn screening programs represent a unique resource for examining pre-diagnostic 25-(OH)D in relation to childhood cancers and allows for focus on the impact of vitamin D during the in utero time period. The long-term goal is to understand the pathogenesis of CBT so that interventions can be developed to reduce the burden of this disease among children. The overall objective for this application, which is a step toward attainment of the long term goal, is to examine the association between neonatal 25-(OH)D, as measured in DBS, with risk of CBT. The central hypothesis of the proposed study is that vitamin D deficiency during pregnancy is associated with increased risk of CBT. The hypothesis will be tested by pursuing two specific aims 1) Evaluate among 250 childhood brain tumor cases and 250 controls the association between 25-(OH)D, as measured in DBS as a marker of gestational circulating vitamin D levels, and the risk of CBT; 2) In exploratory analyses, determine if the association between 25-(OH)D and brain tumor risk differs by sex, race/ethnicity, prenatal smoking, maternal SES, brain tumor histology, birth weight, gestational age and month and season of birth. This study is innovative because it will, for the first time, examine circulating vitamin D levels as predictors of CBT risk by using measurements in DBS as markers of in utero vitamin D levels. The proposed research is significant because it is expected to provide valuable data that will ultimately lead to efficacious targets for interventions to mitigate the occurrence of CBT. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because few modifiable risk factors have been identified for childhood brain tumors, the leading cause of cancer death among children. Vitamin D deficiency is a promising modifiable risk factor that may ultimately be a target for intervention to prevent this disease. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to fostering research that will ultimately protect and improve human health.